International Scholarly Research NetworkISRN OrthopedicsVolume 2011, Article ID 504393, 14 pagesdoi:10.5402/2011/504393

Review Article

The Epidemiology and Demographics ofLegg-Calve-Perthes’ Disease

Randall T. Loder1, 2 and Elaine N. Skopelja3

1 Section of Orthopedic Surgery, Riley Hospital for Children, ROC 4250, 705 Riley Hospital Drive, IN, Indianapolis 46202, USA2 Department of Orthopaedic Surgery, Indiana University, Indianapolis, IN 46202, USA3 Ruth Lilly Medical Library, School of Medicine, Indiana University, Indianapolis, IN 46202, USA

Correspondence should be addressed to Randall T. Loder, rloder@iupui.edu

Received 15 May 2011; Accepted 20 June 2011

Academic Editor: S. Garcıa-Mata

Copyright © 2011 R. T. Loder and E. N. Skopelja. This is an open access article distributed under the Creative CommonsAttribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work isproperly cited.

The etiology of Legg-Calve-Perthes’ disease (LCPD) is unknown. There are many insights however from epidemio-logic/demographic information. A systematic medical literature review regarding LCPD was performed. The incidence rangesfrom 0.4/100,000 to 29.0/100,000 children <15 years of age. There is significant variability in incidence within racial groups and isfrequently higher in lower socioeconomic classes. The typical age at presentation ranges from 4 to 8 years (average 6.5 years), exceptfor children from the Indian subcontinent (average 9.5 years). There is a mild familial component. The children demonstrateimpaired growth in height, skeletal age, and birth weight. This impaired growth coincides with an age appropriate reducedsomatomedin A activity and decreased levels of IGF. LCPD can be associated with abnormalities in the coagulation cascade,including an increase in factor V Leiden mutation, low levels of protein C and/or S, and decreased antithrombin activity. There isdecreased turnover in type I collagen and synthesis of type III collagen, as well as reduced levels of urinary glycosaminoglycans inthe active phases of the disorder. Subtle abnormalities in the opposite hip and other minor/major congenital defects are reported.Children with LCPD are active and score abnormally in certain standardized psychological tests.

1. Introduction

Legg-Calve-Perthes’ disease (LCPD) is an idiopathicosteonecrosis of the proximal capital femoral epiphysisin children. The epiphysis undergoes collapse, resorption,reossification, and eventual healing. The healed hip mayrange from an essentially normal contoured femoralhead (Stulberg I) to one with incongruous incongruity(Stulberg V). As with any pathologic process, LCPD goesthrough a course of disease denoted by the Waldenstromstages, which are synovitic, avascular, fragmentation(collapse), reossification (healing), and healed (residual).The magnitude of epiphyseal involvement is determined bythe Catterall class [1], Salter-Thompson group [2], and/orlateral pillar group [3]. The Catterall class is determined onboth anteroposterior and frog-lateral radiographs duringthe stage of maximum fragmentation, the Salter-Thompsongroup is determined on the frog-lateral radiograph during

the avascular/precollapse stage using the subchondralcrescent fracture, and the lateral pillar classification isdetermined on the anteroposterior radiograph during earlyfragmentation.

2. Materials and Methods

There are many epidemiologic and demographic findings inLCPD. A systematic review of LCPD was performed. LCPDhas been known by at least 22 different names since its firstdescription in the late 19th and early 20th centuries [4]. Since1963, the official medical subject heading (MESH) used bythe National Library of Medicine is Legg-Perthes’ disease,but many other names had been previously used. To ensurecapture of all the published literature, older terms were alsosearched as keywords or keyword phrases. Therefore, theterms used to search for LCPD were arthritis deformansjuvenilis, Calve-Perthes disease, coxa plana, femoral head

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necrosis, juvenile chondroepiphysitis, Legg-Calve-Perthesdisease, Legg-Perthes disease, Legg’s disease, osteochondritisdeformans juvenilis, osteochondritis deformans juveniliscoxae, osteochondritis juvenilis, osteochondrosis of capitalepiphysis of femur, Perthes disease, and pseudocoxalgia.

The databases searched were PubMed (http://www.ncbi.nlm.nih.gov/pubmed/), Ovid Medline, EMBASE, World-Cat (books and theses) (http://firstsearch.oclc.org/), andIndexCat (Index Catalogue of the Library of the Surgeon-General’s Office) (http://www.indexcat.nlm.nih.gov/). Exclu-sion criteria were those manuscripts discussing surgery,therapy, rehabilitation, and any foreign language articleswithout an English abstract. Individual journals were alsosearched for articles published prior to 1996 that predateelectronic Medline indexing, including Journal of Bone andJoint Surgery (American and British), Clinical Orthopaedicsand Related Research, and Acta Orthopaedica Scandinavica.Age groups were limited to those <18 years old. Duplicatecitations were removed. The dates for the search were 1880–1961 for IndexCat, 1900–2009 for WorldCat, 1948–1965 forOldMedline, and 1950–February 2010 for Ovid Medline.

This search resulted in 1124 unique citations. These1124 manuscripts were reviewed to find those that discussedany of the topics regarding etiology, epidemiology, demo-graphics, incidence, prevalence, race, gender, family history,genetics, inheritance, age, bone age, weight (either birthweight or normal weight), height, growth, maturation, otheranthropometric characteristics, hormone/endocrine, smok-ing, coagulation, fibrinolysis, congenital anomalies, collagen,immunoglobulin, opposite hip, behavior/psychology, sea-sonal variation, and infection. Of these 1124 manuscripts,144 provided ample information and are the contents of thispaper.

3. Results

3.1. Incidence. The conventional quotation for the incidenceof LCPD is the number per 100,000, usually for age < 15years. The incidence of LCPD ranges widely, from 0.4 inEastern India (Vellore-Taluk area) to 29.0 (Table 1) in theFaroe Islands (North Atlantic ocean). Significant variabilityexists within countries, cities, and ethnic groups. Raceis classified using the definitions of Eveleth and Tanner:Caucasians, Africans in Africa and of African ancestry, Asi-atics (Amerindians, Hispanics, Indonesian-Malays), Indo-Mediterraneans (inhabitants of the Near East, North Africa,and Indian subcontinent), and Australian Aborigines andPacific Island peoples [23].

3.2. Whites

3.2.1. British Isles. The incidence ranges from 5.5 in Wessex,England [13], to 15.6 in Liverpool, England [21]. Theincidence in 3 different regions of England [13] was 5.5 inthe Wessex Health District, 7.6 in the Trent Health District,and 11.1 in the Mersey Health District (including Liverpool)(Figure 1(a)). In Liverpool, the incidence in the inner city

was higher (21.1) compared to the surrounding areas (13.1—outer Liverpool, 14.6—Knowsley district, 11.9—Sefton dis-trict) [21] (Figure 1(b)) implying that the incidence islower in less populated or more rural areas. However, insouthwest Scotland [20], the incidence was higher in lesspopulated areas (17 to 30) compared to more populatedareas (4.5). In Yorkshire, England, which has a substantialrural population, the average incidence was 6.1, with largegeographical variations unexplainable by differences betweenurban and rural populations [15]. The East Riding area ofYorkshire, located on the best agricultural land, had no cases[15].

Many authors have noted differences in incidence bysocial class and/or inner city/urban/rural location. In theseminal epidemiologic study of 310 children in Edinburghand Glasgow, Scotland [24], there was a higher than expectedproportion of children with LCPD in lower socioeconomicclasses; the same was noted in Liverpool [25] (Figure 2(a)).The incidence in the Liverpool inner city within the highestsocially deprived area was 31.7 and 10.3 for the lowest; in theouter city the incidence was 21.8 within the highest sociallydeprived area and 7.4 for the lowest [21] (Figure 2(b)). InNorthern Ireland [19], the highest incidence is in the mostdeprived rural location (16.1), over twice that in the leastdeprived rural location (7.1). In Southwest Scotland [20], theincidence was 33.6 in the most deprived areas and 7.8 in theleast deprived areas; the 33.6 incidence is the highest foundto date in any series/publications. However, in Glasgow, therewas no association of LCPD incidence and social class [26].In general, the incidence of LCPD in the British Isles ishigher in lower socioeconomic classes and variable regardingrural/urban location (Figure 2(b)).

3.2.2. Scandinavia. The incidence is 8.5 in Uppsala, Sweden[16], and 9.2 in Norway [17]. Within Norway, similar tothe British Isles, there is significant variability; the lowestincidence in the north (5.4) and the highest in the center andwest (10.8 and 11.3).

3.2.3. North America. In British Columbia [12], the inci-dence was 5.10 and, in Massachusetts, [14] 5.7.

3.2.4. Africa. In Eastern Cape, South Africa [6], the incidencein Whites is 10.8; in the urban areas (Port Elizabeth andUitenhage), it is ∼2 times greater than in rural areas. Thisurban-rural dichotomy was noted overall (3.85 versus 1.1)and when separated by race (12.6 versus 6.0 for Whites, 2.2versus 1.4 for mixed African-White, and 0.7 versus 0.28 forAfricans).

3.3. Indo-Malays. In Japan [7], the incidence was 0.90.In Bradford, England, the incidence was 4.6 in Caucasianchildren and 0.63 in Indo-Malay children [27]. In Korea[9], the incidence was 3.8 and lower in the greaterGwanju metropolitan areas compared to the rural Chonnamprovince (3.2 versus 4.3).

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Table 1: Incidence of Legg-Calve-Perthes’ disease∗.

Study Year City, country Region Ethnicity No Pts Incid

Joseph et al. [5] 1988 Vellore, India Asia Indo-Med (Indian) 4 0.4

Purry [6] 1982 Eastern Cape, South Africa Africa Black 6 0.45

Kim et al. [7] 2006 Japan Asia Indo-Malay (Japanese) 711 0.9

Purry [6] 1982 Eastern Cape, South Africa Africa Mixed 11 1.73

Ebong [8] 1977 Nigeria Africa Black 10 1.8

Rowe et al. [9] 2005 Chonnam, Korea Asia Indo-Malay (Korean) 84 3.8

Joseph et al. [5] 1988 Udupi, India Asia Indo-Med (Indian) 138 4.4

Wijesekera [10] 1984 Kurunegala, Sri Lanka (Ceylon) Asia Indo-Med (Indian) 76 3.96

Thompson and Leong [11] 1978 Hong Kong Asia Indo-Malay (Chinese) 32 4.5

Gray et al. [12] 1972 British Columbia, Canada North America White 379 5.1

Barker et al. [13] 1978 Wessex, England British Isles White 34 5.5

Molloy and MacMahon [14] 1966 Massachusetts North America White† 86 5.7

Hall and Barker [15] 1989 Yorkshire, England British Isles White 101 6.1

Barker et al. [13] 1978 Trent, England British Isles White 78 7.6

Moberg and Rehnberg [16] 1964 Zealand, Denmark Scandinavia White NA 8.0

Moberg and Rehnberg [16] 1992 Uppsala, Sweden Scandinavia White 51 8.5

Moberg and Rehnberg [16] 1964 Jutland, Denmark Scandinavia White NA 9.0

Wiig et al. [17] 2006 Norway Scandinavia White 425 9.2

Purry [6] 1982 Easter Cape, South Africa Africa White 38 10.8

Margetts et al. [18] 2001 Liverpool, England British Isles White 122 11.1

Barker et al. [13] 1978 Mersey, England British Isles White 68 11.1

Kealey et al. [19] 2000 Northern Ireland British Isles White 313 11.6

Pillai et al. [20] 2005 Dumfries, Scotland British Isles White 40 15.4

Hall et al. [21] 1983 Liverpool, England British Isles White 157 15.6

Niclasen [22] 1974 Faroe Islands, Denmark Scandinavia White 43 29.0∗

(per 100,000 children <15 yrs old).†one of the 86 children was African.NA: not available.

3.4. Indo-Mediterraneans

3.4.1. India/Sri Lanka. There is a 10-fold variability inincidence in India; 0.4 in the east (Vellore Taluk) [5] to 4.4in the west (Udupi Taluk). In Sri Lanka (Kurunegala district)the incidence is 3.96 [10], and all 76 children with LCPD werefrom lower income groups [10].

3.5. Africans. True LCPD (excluding sickle cell hemoglobin-opathy) is extremely rare in Africans. In Eastern Cape, SouthAfrica [6], the incidence is 0.45 and rises to 1.73 in childrenof mixed African/Caucasian ancestry. The incidence is 1.8in Nigeria [8]. In Togo, there were 22 cases of LCPD in29620 children attending two Togolese hospitals over a 7-year period, indicating the rarity of the disorder. One of 86children in Massachusetts [14] was African, and two of the188 children in Connecticut was African [28].

3.6. Other Demographics (Age, Gender, Laterality,

Family History)

3.6.1. Age, Gender, Laterality, LCPD Severity. The average ageis 6.5 years, with a typical age range of 4 to 8 years (Table 2).The average age for Indian children is 9.5 years, for Nigerian

children 10.3 years, and for all others 6.3 years. LCPD is morecommon in boys (81.4%) than girls (18.6%) and mostlyunilateral (89.2%). Right and left hip involvement is similar(46.5% and 53.5%). In 1638 hips (Table 3), 112 (6.8%) wereCatterall class I, 295 (18.0%) class II, 710 (43.3%) class III,and 521 (31.8%) class IV. In 1671 hips, 236 (14.1%) werelateral pillar group A, 971 (58.1%) B and B/C border, and464 (27.8%) C.

3.6.2. Family History/Genetics. A positive family historyhas been noted by many [7, 24, 27, 28, 37–41]. Quotedpercentages are 4.5% [7], 7% [28], and 8% [27]. There arealso reports in siblings [42, 43]. The recurrence risk was2.6% for siblings and offspring in a review of the familyhistories of 842 English children with LCPD [44], arguingfor a multifactorial inheritance pattern. The proportion ofthe 842 children having a 1st degree relative with LCPD was1.6%, a 2nd degree relative 0.27%, and a 3rd degree relative0.27%; all higher than the average English incidence. InSouth Wales [45], the risk of LCPD in siblings was under 1%and of an affected parent 3%. There are several case reportsof LCPD transmitted through several generations [40, 46].In the Faroe Islands [47], an isolated genetic community, anaccumulation of both LCPD and developmental dislocation

4 ISRN Orthopedics

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ISRN Orthopedics 5

KnottsSouthYorks

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(b)

Figure 1: Maps demonstrating various incidences of LCPD in different regions of England. (a) Incidence of LCPD in 1976 per 100,000children aged 14 years and under in three regions of England. Map of England taken and adapted from the National Policing ImprovementAgency, located at http://maps.police.uk/, with permission (Data from [13]). (b) Average yearly incidence of LCPD per 100,000 childrenaged 14 and under in the Liverpool administrative area. Map of Merseyside area taken and adapted from the National Museums Liverpoollocated at http://www.liverpoolmuseums.org.uk/maritime/exhibitions/magical/placenames/index.asp, with permission (Data from Hall etal. [21] and Barker et al. [13] (Wirral)).

Table 3: Severity of epiphyseal involvement in Legg-Calve-Perthes’ disease.

Study Year LocationCatterall class Lateral pillar group

I II III IV A B BC B + BC C

Rosenfeld et al. [29] 2007 Dallas, TX 7 108 30 138 43

Catterall [1] 1971 London, England 31 31 22 13

Guille et al. [32] 1998 Wilmington, DE 37 120 228 233 155 204 204 204

Wang et al. [33] 1990 Taipei, Taiwan 0 7 19 21

Kim et al. [7] 2006 Japan 30 103 352 210 68 350 350 157

Herring et al. [35] 2004 USA 6 218 61 279 60

Wijesekera [10] 1984 Kurunegala, Sri Lanka 13 21 33 11

Chacko et al. [36] 1986 Karnataka, India 1 13 56 33

Total 112 295 710 521 236 880 91 971 464

Percentage 6.8 18.0 43.3 31.8 14.1 52.7 5.4 58.1 27.8

of the hip was noted in certain families; it remains to bedetermined if this is genetic, environmental, or both. Othersnote no significant association with family history [24, 33].

There are case reports of LCPD in twins, both monozy-gotic [48–51] and dizygotic [52], as well as three female 1stdegree relatives [53]. These dated studies could not assess for

genetic markers, and thus it is unknown if this represents atrue genetic pattern or simply the statistical chance of siblingsdeveloping the same disease. Wynne-Davies and Gormley[24] described 6 sets of twins with only one of the twinshaving LCPD.

6 ISRN Orthopedics

I, II, IIIN(highest) IIIM

IVV (lowest)

All otherwards

InnerLiverpool0

5

10

15

20

25

30

35

Inci

den

ce

Social class

Incidence of LCPD in Liverpool

(a)

Incidence of LCPD in the British Isles

0

5

10

15

20

25

30

35

Lowest deprivation Highest deprivation

Social deprivation

Inci

den

ce

Liverpool inner cityLiverpool outer wardsSouthwest Scotland

Northern Ireland RuralNorthern Ireland Urban

(b)

Figure 2: (a) Incidence of LCPD (100,000 children per year ≤14years of age) by social class in location in Liverpool (Data from Hallet al. [21]). (b) Composite incidence of LCPD (100,000 children peryear <14 years of age) by highest and lowest deprivation indicesseparated by rural and urban locations in the British Isles (Datafrom Hall et al. [21], Kealey et al. [19], and Pillai et al. [20]).

Several studies show associations with certain HLA types.A positive association was noted with HLA-A1 [54, 55] andHLA-A9, HLA-A10, and HLA-B27 [56]. A protective effect wasseen with HLA-A2 and HLA-Cw3; the incidence of LCPD wasless in those types [57]. Two studies found no differences inHLA types [58, 59]. There is no apparent association betweenABO and Rh blood groups [60].

3.7. Perinatal Factors (Parental Age, Birth Order/Presentation,Birth Weight). Both parents of children with LCPD wereolder than the normal population (31.7 versus 28.8 years for

the fathers, 28.9 versus 26.9 for the mothers) in one study[24], with no differences noted in parental age by others[28, 33, 61].

LCPD was more frequent in the 3rd born or olderchildren [24] in one study, while others noted no differ-ences [33]. Children with LCPD are more commonly bornbreech—10.7% compared to 2–4% in the normal population[24]. A lower birth weight was noted in children with LCPD[62, 63]; 7.1 lbs in 70 children with LCPD and 7.8 lbs in 70control children without LCPD [62]. In 5 sets of twins, thesmaller twin at birth developed the LCPD [63]; the averagediscordance in birth weight was 13.4% (range 7.1 to 23.5%).Others note no differences in birth weight [24, 33, 61].

3.8. Impaired Growth, Anthropometric Differences, and

Skeletal Maturation

3.8.1. Impaired Growth and Anthropometric Differences.Height retardation was noted in 185 Ohio children withLCPD [64], even when accounting for parental height; bodyweight was average or above average. In Scottish children,a greater proportion of LCPD children have diminishedheight (<10th percentile) with no differences for weight[24]. In 76 Sri Lanka children with LCPD, 46% were belowaverage height at presentation [10]. In 109 Japanese childrenwith LCPD, 97 (89%) were below the mean in height [65].Children with LCPD are shorter at birth and remained soduring the phases of LCPD and adulthood [66, 67]; boys were4.4 cm shorter and girls 2.5 cm shorter than their norms [66].No height or weight differences were found in Irish [68] andJewish children with LCPD [69].

Skeletal growth is progressively impaired in a caudaldirection. Rostral sparing is documented by normal headgrowth [70] with increasing growth retardation in a caudaldirection: biacromial width was less reduced than standingheight; forearm and hand showed more impaired growththan the upper arm; the feet showed more impaired growththan the leg. This impaired growth most severely affects thefeet [24, 71]. Growth retardation in LCPD children fromrural India [72] is identical to English children.

3.8.2. Skeletal Maturation. Aside from one study in Jewishchildren with LCPD [69], all others note delayed bone agein LCPD. In 182 children with LCPD, many were <3rdpercentile bone age, which was more common in boys thangirls [76]. In 125 of 140 (89%) children with LCPD [28]bone age was delayed. Bone age was at least 3 months lessin 83% of children [67]. This is seen [75] with both theGreulich-Pyle hand-wrist assessment [73] and the Oxfordpelvis method [74] of determining bone age (Figure 3). Theaverage chronologic age for both boys and girls was 8.2 years;for boys, the average hand-wrist bone age was 7.4 years andaverage pelvic bone age 5.9 years, and, for girls, the averagehand-wrist bone age was 6.9 years and average pelvic bone7.0 years [75]. Carpal maturation was delayed in 125 childrenwith LCPD; the most severe delay was at 3 to 5 years of age[77]. In a study of 27 girls with LCPD at the time of diagnosis[78], bone age (Tanner Whitehouse 2 method) was delayed

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3

4

5

6

7

8

9

10

11

12

13

6 7 8 9 10 11 12

Chronological age

Bon

eag

e

OX AGGP AG

Figure 3: Chronologic age as a function of bone age in 100 childrenwith LCPD. Both the hand-wrist bone of Greulich and Pyle (GP AG)[73] as well as the Oxford pelvic bone age (OX AG) [74] are shown(Data from the study of Loder et al. [75]).

an average of 1.4 years for the radius/ulna and 1.9 years forthe carpals. A greater delay in bone age is associated withmore severe LCPD [79]. Children with transient synovitisshow minimal delay in bone age compared to those withLCPD (7 months versus 23 months) [80].

In non-Caucasians, bone age was delayed 31.8 monthsin 17 of 25 Formosan (68%) children with LCPD [33]. InHong Kong, all Chinese children with LCPD had a bone agelower than the mean [11]. In Korean children, bone age wasdelayed 10.4 months in boys and 4.6 months in girls [9].In 21 Japanese LCPD children, delayed bone age was notedin all [65]. In 76 Sri Lankan children, 78% demonstratedskeletal retardation [10]. In Mexican children (Hispanic-Amerindian), bone age was delayed 28 months in childrenwith LCPD between the ages of 6–10 years [81].

Skeletal standstill (no increase in bone age with increas-ing chronologic age) occurs in LCPD [75, 76] and resolvesafter the LCPD has healed [80].

3.9. Endocrine Dysfunction. Postnatal skeletal developmentis regulated by growth hormone, whose effects are partlymediated by somatomedins. Somatomedins stimulate car-tilage activity resulting in cell proliferation and hypertro-phy. In Japan, the incidence of LCPD was 70 in growth-hormone-deficient children [82] compared to 0.9 in thenormal population [7]. Serum growth hormone response toinsulin-induced hypoglycemia is reduced in boys with LCPDcompared to those with constitutional short stature [83].The primary somatomedin responsible for postnatal skeletalmaturation is somatomedin C insulin-like growth factor(IGF-1). Somatomedin deficiency may result in impairedskeletal maturation, a well-known phenomenon in LCPD.Somatomedin A [84] and C [65] deficiency has been notedLCPD. Somatomedin activity normally increases with age ingrowing children, but this does not occur in children withLCPD [85, 86]. Plasma levels of IGF-1 were reduced the first

2 years after the diagnosis of LCPD [87], but with normallevels of IGF-binding protein [88]. Low levels of IGF-1 wereconfirmed by Crofton et al. [89], who also noted abnormalcollagen turnover in the acute stages of LCPD. In plasma,nearly all the IGF-1 is bound to specific binding proteins,which for IGF-1 is the IGF-binding protein 3 (IGFBP3).Decreased levels of IGFBP in children with LCPD have beenseen but with normal levels of IGF-1 [90]. No abnormalitiesin IGF-1 or IGFBP concentrations have been encountered byothers [68, 83, 91, 92] in children with LCPD.

Early studies [93, 94] noted an association with hypothy-roidism and LCPD but not seen in more recent studies [68,83, 95–98]. No abnormalities in adrenal function (cortisol)[68, 83] or cholesterol [96] have been noted.

3.10. Smoking, Hypofibrinolysis, and LCPD. Passive smokeexposure during pregnancy has been correlated with LCPD.This was first noted in Massachusetts [62]; maternal smokingwhile pregnant was present in 63% of LCPD and 43% ofcontrol cases. This was confirmed in Sweden [99]; maternalsmoking during pregnancy increased the odds of developingLCPD in the child by 1.44 if the mother smoked <10cigarettes per day, and by 2.1 when ≥10 cigarettes per day. Itwas also noted that children with a birth weight <1500 gmshad a 2.4 times increased risk of developing LCPD.

An increase in LCPD in children exposed to passivesmoke after birth has also been noted. In children withLCPD [100], 63.9% had at least one smoker living in thechild’s household with a mean of 1.03 smoker years peryear of life exposure to smoke; in control children, 39.6%had at least one smoker living in the child’s house witha mean of 0.48 smoker years per year of life exposure tosmoke. No association was noted between lower income andLCPD. This association with passive smoke exposure wascorroborated in Spain [101], where 79% of LCPD childrenwere passive smokers compared to 43% of controls. Theodds ratio for a child, after controlling for age and gender,of developing LCPD when exposed to passive smoke was5.3 (95% CI 2.9–9.7). There were no associations betweenpassive smoking and age of child, Catterall class, or finalStulberg result. In another study of 39 children with LCPD[102], 24 had exposure to second hand smoke, some evenin utero (17 of the 24). Of the children with LCPD andsmoke exposure, 48% had low stimulated tissue plasminogenactivator activity, compared to only 7% of the children with-out smoke exposure. In Georgia [103], children exposed topassive smoke were 5.6 (95% CI 2.0–12.0) times more likelyto develop LCPD than those not exposed. This was stronglyassociated with a polymorphism in the β-fibrinogen geneG-455-A, which results in increased fibrinogen levels, thusleads to thrombotic/coagulation abnormalities in childrenwith LCPD (Figure 4).

Factor V Leiden mutation discovered in Leiden, Nether-lands [104], results in production of factor V that cannot beinactivated by activated protein C. This leads to a persistenceof circulating activated factor V with continued activationof the coagulation cascade and a hypercoagulable state.Families with LCPD and factor V Leiden mutations have

8 ISRN Orthopedics

ProcoagulantsIntrinsic pathway

Damaged surface

XII

XI

IX

XIa

XIIa

IXa

VIII VIIIa

Extrinsic pathway

Trauma

Tissuefactor

VIIa

TFPI

Antithrombin III

Antithrombin III

Active protein C

Thrombomodulin

ThrombomodulinProtein S

Protein C+

X XXa

VVa

Prothrombin Thrombin

Fibrin

XIIIa

Fibrin clot

Commonpathway

FibrinDegradation

Products

Anticoagulants

Plasmin

Tissue plasminogenActivatorsXIIa, XIa

Global fibrinolyticactivity

TFPI

Antithrombin III

Antithrombin III

Thrombomodulin

Active protein C, SFactor V leiden

Perthes’ disease

Coa

gula

tion

Fibr

inol

ysis

VII

Fibrinogen

Plasminogen

Figure 4: The coagulation and fibrinolytic cascade as it relates to children with LCPD. The abnormalities in this cascade in children withLCPD are shown in the far right column. TFPI: tissue factor pathway inhibitor.

been described [105, 106]. In nonfamilial LCPD, a factorV Leiden mutation has been noted by many; 12.5% [107]and 10.6% in children with LCPD [108] in studies withoutcontrols. In studies with controls, these values are 30% inLCPD and 1.87% in controls [109], 11% in LCPD and4% in controls [110], 9% in LCPD and 5% in controls[111], and 4.9% in LCPD and 0.7% in controls [112].Children with the most severe LCPD (Catterall IV) werehomozygous for factor V Leiden mutation [108]. High levelsof anticardiolipin antibodies (26% versus 11%) have alsobeen noted [110]. The OR of developing LCPD with factor VLeiden mutation in two studies are 22.5 [109] and 3.3 [113];the OR of developing LCPD with ≥ abnormalities in factorV or anticardiolipin antibody is 3.29 [110].

Other coagulation abnormalities exist in LCPD. Throm-bophilia and hypofibrinolysis were noted in 8 children[114] in 1994. A subsequent investigation noted that 75%of 44 children with LCPD had coagulation abnormalities[115]; thrombophilia (a deficiency in antithrombotic factorC or S, with an increased tendency towards thrombosis)in 23 children; increased lipoprotien(a) (a thrombogeniclipoprotein associated with osteonecrosis in adults) in 7children; hypofibrinolysis (reduced ability to lyse clots) in 3children. In another study, only 14 of 64 children (22.5%)with LCPD had entirely normal coagulation measures [107]with resistance to activated protein C the most common

abnormality (23 of 64). A 3.8 times increased risk for LCPDwith low levels of protein C has been found [111]. Protein Cactivity is also lower in LCPD [116, 117]. Both protein C andantithrombin activities were lower in LCPD than controls[117]; a family history of hereditary thrombophilia washigher in LCPD than controls. LCPD was increased 2.8 timeswith protein S deficiency and 7.5 times with elevated factorVIII levels [113]. Others note no coagulation abnormalitiesin LCPD [116, 118–127].

Another fact supporting a hypercoagulable state in LCPDis tissue factor pathway inhibitor (TFPI). TFPI is an impor-tant natural anticoagulant molecule that downregulates thetissue factor dependent coagulation pathway. A deficiencyleads to a prothrombotic state, and over expression maybe a protective mechanism against ongoing local microvas-cular events. TFPI concentrations in children with LCPDwere significantly higher (56.8 ng/mL) compared to controls(37.3 ng/mL) [128]. This is interpreted as a physiologicresponse to a hypercoagulable state; an increased TFPI isnatural anticoagulation. Increased blood viscosity in LCPDis reported [129]; thus vascular occlusion may simply be dueto fluid mechanic properties [129].

After thrombosis, the body attempts to lyse the clot.Fibrinolysis is mediated in part by thrombomodulin, anendothelial cell membrane-associated glycoprotein whichfunctions in activation of the anticoagulant systems. In

ISRN Orthopedics 9

0

5

10

15

20

25

30

35

40

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ovit

ic

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on

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ssifi

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on

Res

idu

al

Waldenstrom stage

DP

D/C

RE

Ara

tio

(nm

ol/m

mol

)

Figure 5: Urinary DPD/CREA (urinary deoxypyridinoline/creat-inine ratio) in children with LCPD in different Waldenstromstages. The control level is denoted by the hatched line. DPDis a degradation product of type I collagen; a decrease in itsurinary excretion indicates a decrease in bone turnover. Thus,there is decreased bone turnover in children with LCPD duringthe avascular and fragmentation phases of the disease (Data fromWesthoff et al. [131]).

LCPD, thrombomodulin and global fibrinolytic activity areelevated [130]. This is interpreted as a compensatory reactionto the thrombosis in LCPD.

3.11. Other Associations with LCPD

3.11.1. Collagen Metabolism/Genetics and Bone Turnover.Type I collagen is found almost exclusively in bone andcalcifying tissues. Markers of type I collagen degradationare urinary deoxypyridinoline (DPD) and type I collagentelopeptide (ICTP). ICTP is higher in children with LCPDcompared to controls [89], indicating an increase in type Icollagen degradation. The median urinary DPD/creatinineratio in children with LCPD is reduced during the fragmenta-tion stage and returns to normal (if not slightly higher) in thehealed stage [131] (Figure 5). The DPD/creatinine decrease isgreater with more severe LCPD (egg lateral pillar C > lateralpillar B). These findings support a systemic etiology in LCPD.

A marker of type III collagen synthesis is the procollagentype III N-terminal propeptide (P3NP). Type III collagensynthesis is reduced at diagnosis in children with LCPDas demonstrated by very low levels of P3NP. However,there were no controls, and the differences in children withLCPD compared to otherwise normal children in the samegeographic/ethnic/socioeconomic situation are not known.

A recurrent mutation in type II collagen (cartilage col-lagen) in a Japanese family with LCPD [38] has been noted.This mutation amino acid change (p.G1170S) perturbs theGly-X-Y triple-helix of type II collagen. Similar findings werenoted in a Chinese family where a p.Gly1170S mutation ofCOL2A1 resulted in premature hip osteoarthritis, avascularnecrosis of the femoral head, or LCPD, depending upon the

age at onset [39]. In a cohort of nonfamilial children withLCPD, no mutations in the COL2A1 gene were found [124].

3.11.2. Articular Cartilage Markers. Glycosaminoglycans(GAGs) are chains of repetitive disaccharide units linkedwith proteins in the cartilaginous extracellular matrix toform proteoglycans. Upon cartilage degradation, GAGs areeliminated by the kidneys. Elevated urinary GAG levelsindicate increased articular cartilage degradation. Decreasedlevels of urinary GAGs in children with LCPD comparedto normal children or those with transient synovitis havebeen noted [132]. This can be interpreted as either increasedpreservation of the GAGs within the hip or a decrease in thequantity of synovial fluid. Increased levels of proteoglycanfragments and stromelysin in the synovial fluid of childrenwith LCPD have been noted, consistent with a synovitis[133].

3.11.3. The Opposite Hip in Unilateral LCPD. In a reviewof the radiographs of 153 children with unilateral LCPD[134], 48.4% demonstrated irregularity of the epiphysealsurface, flattening, or dimpling of the opposite “normal hip.”In most instances (37%), they were present in the initialradiograph. Similar changes were noted in only 10.4% ofa control group of 153 age and gender-matched childrenusing intravenous urograms. This was interpreted as thecapital femoral epiphysis in the young child being veryvulnerable to stress; the minimal contour irregularities in the“normal hip” represent one end of the spectrum and frankLCPD, the other as the stress response of the capital femoralepiphysis. Another study confirmed that the “unaffected”hip in LCPD demonstrates anterior and lateral flatteningperhaps indicating a constitutional abnormality [135]. In athird study, 15% of the opposite “normal” hips demonstratedphyseal changes, especially decalcification below the physis[136]. The initial radiographs of 125 Japanese children withunilateral LCPD demonstrate delayed ossification of theopposite epiphysis as seen by diminished epiphyseal height[137].

3.11.4. Behavioral/Psychological Issues. Children with LCPDare extremely busy and active. An early study (PhD thesis)discovered that children with LCPD demonstrated a motor-expressive personality, an active approach to life and hadhigher psychosomatic and visceral complaints [138]. Alater study [139] reviewed the behavioral characteristicsof 24 children with LCPD; 33% of children with LCPDhad abnormally high scores in standard psychological childbehavioral questionnaires for profiles associated with atten-tion deficit hyperactivity disorder, greater than the 3–5% ofage matched children. Certain epidemiologic characteristicsof LCPD (gender, socioeconomic status, geographic location,and associated congenital anomalies) are also similar char-acteristics of attention deficit hyperactivity disorder. Thesefindings were confirmed in a recent study of 19 childrenwith LCPD [92]; 8 of 12 school-aged children had negativescores in neuropsychological tests and 5 of the 8 had learningdifficulties at school.

10 ISRN Orthopedics

3.11.5. Miscellaneous Findings. An increase in both majorand minor congenital defects in children with LCPD isknown [61]. These include anomalies of the genitourinarytract and inguinal region [140] and spina bifida occulta[10, 141, 142]. Sacral inclination, decreased lumbar lordosis,and an overall more negative spinal balance with vertebralend plate anomalies have been recently described in the spineof LCPD patients [143].

Low blood manganese levels were noted in children withLCPD in Liverpool [144], but refuted by others [145]. Anincrease in IgG and IgM, but not IgA serum immunoglob-ulin levels in LCPD, are described [146], suggesting thatimmunological mechanisms may mediate certain changes inLCPD. Rubella antibody titers are higher in both mothersand affected children with LCPD [147].

4. Conclusion and Unifying Possibilities

Can these epidemiologic and demographic findings beunified? There clearly is disharmony between cartilage andbone and growth in LCPD as evidenced by progressive caudalgrowth impairment and delays in skeletal maturation, bothinvolving the wrist and the pelvis. The insult on skeletalmaturation appears to occur early in life, perhaps evenprenatally, since there is an increased frequency of minorcongenital malformations in children with LCPD. Thesedelays in maturation (both anthropometric and skeletal age)can be due to a combination of familial and environmentalcircumstances (lower socioeconomic class with malnutrition[148], underlying genetic/collagen defects, or some otherunknown entity). The delay in skeletal ossification resultsin a weaker skeleton that is more susceptible to trauma.A highly active child incurs more skeletal injuries; thismicrotrauma in a biologically susceptible weaker skeletoncreates microfractures in the proximal femoral epiphysisand metaphysis. A hypercoagulable state, due to underlyingabnormalities in the clotting mechanisms and/or exposure topassive smoke, results in increased thrombosis in the proxi-mal femur after microfractures with subsequent necrosis ofthe capital femoral epiphysis and the development of LCPD.

Conflict of Interests

The author’s otherwise have no financial interests with anyother organizations or bodies.

Disclosure

As a systematic literature review, Institutional Review Boardapproval is not applicable. This was the 2nd of threepresentations on the epidemiology and demographics ofPediatric Hip Disorders given at the AO North AmericanSymposium on Surgical Preservation of the Hip, SquawValley, California, January 2009.

Acknowledgment

This study was supported in part by the Garceau Profes-sorship Endowment, Department of Orthopaedic Surgery,

Indiana University School of Medicine, and the George RappPediatric Orthopaedic Research Endowment, Riley Chil-dren’s Foundation, Riley Children’s Hospital, Indianapolis,Indiana.

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